Nanostructure Engineering Is Another Approach Toward Membrane-Active Antimicrobials with Desirable Activity and Selectivity

纳米结构工程是开发具有理想活性和选择性的膜活性抗菌剂的另一种方法

• 批准号: 1810767
• 负责人: Hongjun Liang
• 金额: $ 45.79万
• 依托单位: Texas Tech University Health Science Center
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1810767&HistoricalAwards=false
• 关键词: Nanostructure; Engineering; Another; Approach; Toward

Abstract # DMR ? 1810767Non-Technical Summary Antibiotic-resistant superbugs that elude one or more traditional antibiotics are causing a public health crisis. Membrane-active antimicrobials represent a new family of promising antibiotic materials to address this crisis. They include a wide variety of small molecules, polymers, polypeptides, self-assembled structures, and organic-inorganic hybrid materials that kill bacteria by disrupting bacterial membranes. Since this mode of damage does not target specific biosynthetic pathways, the possibility of inducing bacterial resistance is greatly reduced. However, most current designs of membrane-active antimicrobials are not ready for applications yet because their hydrophobicity believed to be indispensable for breaking bacterial membranes also damages mammalian cells, which gives rise to their unacceptable toxicity. A critical but poorly understood question is how to design hydrophilic membrane-active antimicrobials that kill bacteria specifically without having to breach the hydrophobic cell membrane in general. Recent discovery of various membrane-active antibiotic nanomaterials suggests that nanostructure engineering could be another approach to develop membrane-active antimicrobials. The objective of this award is to adapt materials engineering, chemistry, and biological tools for the development of hydrophilic nanostructured antibiotic materials, and to elucidate the role of nanostructures on bacterial membrane remodeling. The successful outcomes of this award will pave the way for a potential paradigm shift to develop novel antibiotic materials with desirable activity, selectivity, and biocompatibility to fight bacterial resistance. Integrated with the research activities is a multi-tiered antimicrobial education program that will bring broad societal awareness on antibiotic resistance, and train next generation of scientists on the development of new antibiotic materials. Technical SummaryThe overall objective of this award is to adapt materials engineering, chemistry, and biological tools for the development of nanostructured membrane-active antibiotic materials (i.e., "nanoantibiotics"), and to elucidate the role of nanostructures on bacterial membrane remodeling. The central hypothesis is that hydrophilic linear-chain polymers that do not breach the hydrophobic membrane interior but have poor antimicrobial activity can be transformed into potent antibiotic materials with high selectivity when assembled into nanostructures. This award will identify the role of multivalent interactions that drive this transformation, elucidate how nanostructure itself helps regulate antimicrobial activity and selectivity, and determine the feasibility of triple selectivity in the design of nanoantibiotics that will disintegrate and become inactive in response to environmental stimuli. This award will help open a door to transform diverse hydrophilic polymers that have excellent biocompatibility but weak antibiotic activity into potent nanostructured antibiotic materials. It will also reveal how to use physical dimensions of nanostructured membrane-active antibiotic materials as a simple tool to tune their activity and selectivity, potentially recruiting the latest development in both the bottom-up and top-down nanostructure engineering into antibiotic designs. Finally, it will examine a prototypical design of nanoantibiotics with dismantling "switch", shedding light on how to turn off antimicrobial activity "on demand" by disassembling antibiotic nanostructures after their service, hence reducing the prolonged presence of residue antibiotics in natural habitats that not only helps bacteria develop resistance, but also adversely impacts the ecosystems. This award will provide abundant training opportunities for postdoc, graduate and undergraduate students, and K12 participants in the interdisciplinary area of biology, chemistry, and materials science and engineering, support educational development on membrane-active antibiotic materials, and promote broad societal awareness on antibiotic resistance and antibiotic materials to diverse participants at all levels.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

抽象＃DMR？ 1810767 non-technical摘要抗生素抗生素的超级细菌，一种或多种传统的抗生素正在造成公共卫生危机。膜活性抗菌剂代表了一种有希望的抗生素材料的新家族，以解决这一危机。它们包括多种小分子，聚合物，多肽，自组装结构以及有机无机杂交材料，这些杂交材料通过破坏细菌膜来杀死细菌。由于这种损伤模式并非针对特定的生物合成途径，因此诱导细菌耐药性的可能性大大降低了。然而，膜活性抗菌剂的大多数设计尚未准备好用于应用，因为疏水性认为它们对于破坏细菌膜是必不可少的，也损害了哺乳动物细胞，这会引起其不可感知的毒性。一个关键但知之甚少的问题是如何设计亲水性膜活性抗菌剂，这些抗菌剂特异性地杀死细菌而无需一般疏水细胞膜。最近发现各种膜活性抗生素纳米材料的发现表明，纳米结构工程可能是开发膜活性抗菌剂的另一种方法。该奖项的目的是调整材料工程，化学和生物学工具，以开发亲水性纳米结构抗生素材料，并阐明纳米结构在细菌膜重塑中的作用。该奖项的成功结果将为潜在的范式转移铺平道路，以开发具有可取活性，选择性和生物相容性的新型抗生素材料，以抵抗细菌耐药性。与研究活动相结合的是一项多层抗菌教育计划，该计划将对抗生素耐药性具有广泛的社会意识，并培训下一代科学家开发新的抗生素材料。技术总结该奖项的总体目标是适应材料工程，化学和生物学工具，用于开发纳米​​结构化膜活性抗生素材料（即“纳米抗生素”），并阐明纳米结构在细菌膜重塑中的作用。中心假设是，不违反疏水膜内部但抗菌活性较差的亲水线性链聚合物可以转化为具有高选择性的有效抗生素材料，当组装成纳米结构中时。该奖项将确定驱动这种转换的多价相互作用的作用，阐明纳米结构本身如何帮助调节抗菌活性和选择性，并确定三重选择性在纳米抗生素设计中的可行性，从而使环境刺激响应纳米抗生素的设计，并变得不活跃。该奖项将有助于打开一扇门，以转化具有出色生物相容性但弱抗生素活性的多种亲水性聚合物，从而成为有效的纳米结构抗生素材料。它还将揭示如何使用纳米结构化膜活性抗生素材料的物理维度作为调整其活动和选择性的简单工具，并有可能招募自下而上和自上而下的纳米结构工程中的最新发展。最后，它将通过拆卸“开关”检查纳米抗生素的典型设计，从而通过拆卸服务后拆卸抗生素纳米结构来阐明如何按需关闭抗菌活性，从而减少了在自然生物中的长期存在，从而减少了残留抗生素的长期影响，但它也会影响细菌的影响。该奖项将为DOC，研究生和本科生提供丰富的培训机会，以及K12在生物学，化学和材料科学和工程跨学科领域的K12参与者，为膜活性抗生素材料的教育发展提供支持，并促进对抗生素和抗生素的统计范围，并促进了对各种各样的统计范围，并在所有级别的参与者中均表现出各种各样的参与者。值得通过基金会的智力优点和更广泛的影响审查标准来通过评估来支持。

项目成果

Extraction and reconstitution of membrane proteins into lipid nanodiscs encased by zwitterionic styrene-maleic amide copolymers

• DOI: 10.1038/s41598-020-66852-7
• 发表时间: 2020-06-18
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Fiori, Mariana C.;Zheng, Wan;Liang, Hongjun
• 通讯作者: Liang, Hongjun

Nanodiscs: a versatile nanocarrier platform for cancer diagnosis and treatment

• DOI: 10.1039/d1cs01074c
• 发表时间: 2022-02-14
• 期刊: CHEMICAL SOCIETY REVIEWS
• 影响因子: 46.2
• 作者: Bariwal, Jitender;Ma, Hairong;Liang, Hongjun
• 通讯作者: Liang, Hongjun

Improved Solubility of Membrane Proteins with zSMA Polymers

使用 zSMA 聚合物提高膜蛋白的溶解度

• DOI: 10.1016/j.bpj.2019.11.1418
• 发表时间: 2020
• 期刊: Biophysical Journal
• 影响因子: 3.4
• 作者: Fiori, Mariana C.;Jiang, Yunjiang;Zheng, Wan;Altenberg, Guillermo A.;Liang, Hongjun
• 通讯作者: Liang, Hongjun

Synthesis of Lysine Mimicking Membrane Active Antimicrobial Polymers

仿赖氨酸膜活性抗菌聚合物的合成

• 发表时间: 2018
• 期刊: Advances in Polymer Sciences and Technology
• 作者: Ankita Arora;Wan Zheng;Hongjun Liang;Abhijit Mishra
• 通讯作者: Abhijit Mishra

SMALPs Are Not Simply Nanodiscs: The Polymer-to-Lipid Ratios of Fractionated SMALPs Underline Their Heterogeneous Nature

• DOI: 10.1021/acs.biomac.3c00034
• 发表时间: 2023-03-22
• 期刊: BIOMACROMOLECULES
• 影响因子: 6.2
• 作者: Kamilar，Elizabeth;Bariwal，Jitender;Liang，Hongjun
• 通讯作者: Liang，Hongjun